For more than 100 years, sub-Saharan Africa has suffered with high rates of endemic meningococcal disease and periodic epidemic epidemics involving over 100,000 cases. In 2010, a low cost serogroup A polysaccharide-protein conjugate vaccine (MenAfriVac) was introduced in the region. The vaccine confers protection against serogroup A (MenA) disease as well as asymptomatic nasopharyngeal MenA carriage, but has no effect on strains with other serogroups that also cause epidemics in the region. Multivalent serogroup A,C,Y and W conjugate vaccines are available in industrialized countries but are not affordable in Sub-Sahara, which is one of the poorest regions of the world. These vaccines also do not prevent disease from MenX strains, which also can cause epidemics in the region. Recently, two MenB vaccines based on Neisserial factor H binding protein (FHbp) have been licensed in the US and Europe. FHbp specifically binds human or non- human primate complement FH. We are developing a novel native outer membrane vesicle (NOMV) vaccine with genetically attenuated endotoxin and over-expressed mutant FHbp with low FH binding (NOMV-FHbp). In a non-human infant primate model, a mutant recombinant FHbp antigen with two amino acid substitutions elicited broader serum bactericidal antibody responses than the control FHbp vaccine that bound FH. In human FH transgenic mice, our NOMV-FHbp vaccine provided broader protection than a licensed multivalent A,C,Y and W conjugate vaccine or the MenB vaccine developed by Novartis that contains FHbp that binds FH. However, FHbp is variable with protein sequences falling into two sub-families, A and B. Our prototype NOMV- FHbp vaccine only contained sub-family B FHbp. Our hypothesis is that including a second sub-family A FHbp in NOMV-FHbp will result in a ?universal? vaccine for Africa against strains with FHbp sub-family A or B, while at the same time expanding coverage against MenB strains worldwide. The goal of this Phase I proposal is to produce a safe, broadly protective, affordable vaccine for use in preventing meningococcal disease generally and in Africa specifically. To accomplish this goal, in Aim 1, we will produce NOMV with over- expressed FHbp from both A and B sub-families. Immunogenicity will be evaluated in established transgenic (Tg) mouse models expressing human FH and functional activity of elicited antibodies in complement-mediated serum bactericidal assays (SBA), which is an established correlate of protection against disease in humans. In Aim 2, we will build upon the success of MenAfriVac by combining it with the new NOMV-FHbp A+B vaccine. The combined vaccine has the potential to ensure coverage against all of the predominant MenA strains while at the same time suppressing the emergence of new pathogenic strains from other serogroups.